tbuckley/cabot-search huggingface dataset:
Constitutive Activation of the Tumor Suppressor p53 in Hepatocytes Paradoxically Promotes Non–Cell Autonomous Liver Carcinogenesis
Authors: Yuki Makino, Hayato Hikita, Kenji Fukumoto, Ji Hyun Sung, Yoshihiro Sakano, Kazuhiro Murai, Sadatsugu Sakane, Takahiro Kodama, Ryotaro Sakamori, Jumpei Kondo, Shogo Kobayashi, Tomohide Tatsumi, Tetsuo Takehara
Journal: Cancer Research (2022)

Abstract In chronic liver diseases (CLD), p53 is constitutively activated in hepatocytes due to various etiologies as viral infection, ethanol exposure, or lipid accumulation. This study was aimed to clarify the significance of p53 activation on the pathophysiology of CLDs. In Kras-mutant liver cancer model, murine double minute 2 (Mdm2), a negative regulator of p53, was specifically deleted in hepatocytes [Alb-Cre KrasLSL-G12D Mdm2fl/fl (LiKM; KrasG12D mutation and Mdm2 loss in the liver)]. Accumulation of p53 and upregulation of its downstream genes were observed in hepatocytes in LiKM mice. LiKM mice showed liver inflammation accompanied by hepatocyte apoptosis, senescence-associated secretory phenotype (SASP), and the emergence of hepatic progenitor cells (HPC). More importantly, Mdm2 deletion promoted non–cell autonomous development of liver tumors. Organoids generated from HPCs harbored tumor-formation ability when subcutaneously inoculated into NOD/Shi-scid/IL2Rγ (null) mice. Treatment with acyclic retinoid suppressed growth of HPCs in vitro and inhibited tumorigenesis in LiKM mice. All of the phenotypes in LiKM mice, including accelerated liver tumorigenesis, were negated by further deletion of p53 in hepatocytes (Alb-Cre KrasLSL-G12D Mdm2fl/fl p53fl/fl). Activation of hepatic p53 was noted in liver biopsy samples obtained from 182 patients with CLD, in comparison with 23 normal liver samples without background liver diseases. In patients with CLD, activity of hepatic p53 was positively correlated with the expression of apoptosis, SASP, HPC-associated genes and tumor incidence in the liver after biopsy. In conclusion, activation of hepatocyte p53 creates a microenvironment prone to tumor formation from HPCs. Optimization of p53 activity in hepatocytes is important to prevent patients with CLD from hepatocarcinogenesis. Significance: This study reveals that activation of p53 in hepatocytes promotes liver carcinogenesis derived from HPCs, which elucidates a paradoxical aspect of a tumor suppressor p53 and novel mechanism of liver carcinogenesis. See related commentary by Barton and Lozano, p. 2824
Inappropriate Sinus Tachycardia: Etiology, Pathophysiology, and Management
Authors: Adnan Ahmed, Naga Venkata K. Pothineni, Rishi Charate, Jalaj Garg, Mehmet Elbey, Carlo de Asmundis, Mark LaMeir, Ahmed Romeya, Poojita Shivamurthy, Brian Olshansky, Andrea Russo, Rakesh Gopinathannair, Dhanunjaya Lakkireddy
Journal: Journal of the American College of Cardiology (2022)

Inappropriate sinus tachycardia (IST) is a clinical syndrome that generally affects young patients and is associated with distressing symptoms. Although the most common symptom is palpitations, it can be accompanied by a myriad of symptoms, including anxiety, dizziness, presyncope, and syncope. The pathogenesis of IST is not well understood and considered multifactorial, with autonomic dysfunction being the central abnormality. IST is a diagnosis of exclusion. Management presents a clinical challenge. The overall efficacy of lifestyle modifications and medical therapy may be limited. Recent advances in catheter and surgical sinus node sparing ablation techniques have led to improvement in outcomes. In addition, increased focus has led to development of multimodality team-based interventions to improve outcomes in this group of patients. In this review, we discuss the mechanistic basis of IST, review current approaches to diagnosis, and outline contemporary therapeutic approaches.
Combined assessment of S‐ and N‐specific <scp>IL</scp>‐2 and <scp>IL</scp>‐13 secretion and <scp>CD69</scp> neo‐expression for discrimination of post–infection and post‐vaccination cellular <scp>SARS‐CoV</scp>‐2‐specific immune response
Authors: Bernhard Kratzer, Larissa C. Schlax, Pia Gattinger, Petra Waidhofer‐Söllner, Doris Trapin, Peter A. Tauber, Al Nasar Ahmed Sehgal, Ulrike Körmöczi, Arno Rottal, Melanie Feichter, Teresa Oberhofer, Katharina Grabmeier‐Pfistershammer, Kristina Borochova, Yulia Dorofeeva, Inna Tulaeva, Milena Weber, Bernhard Mühl, Anna Kropfmüller, Bettina Negrin, Michael Kundi, Rudolf Valenta, Winfried F. Pickl
Journal: Allergy (2022)

Abstract Background Antibody‐based tests are available for measuring SARS‐CoV‐2‐specific immune responses but fast T‐cell assays remain scarce. Robust T cell‐based tests are needed to differentiate specific cellular immune responses after infection from those after vaccination. Methods One hundred seventeen individuals (COVID‐19 convalescent patients: n = 40; SARS‐CoV‐2 vaccinees: n = 41; healthy controls: n = 36) were evaluated for SARS‐CoV‐2‐specific cellular immune responses (proliferation, Th1, Th2, Th17, and inflammatory cytokines, activation‐induced marker [AIM] expression) by incubating purified peripheral blood mononuclear cells (PBMC) or whole blood (WB) with SARS‐CoV‐2 peptides (S, N, or M), vaccine antigens (tetanus toxoid, tick borne encephalitis virus) or polyclonal stimuli ( Staphylococcal enterotoxin, phytohemagglutinin). Results N‐peptide mix stimulation of WB identified the combination of IL‐2 and IL‐13 secretion as superior to IFN‐γ secretion to discriminate between COVID‐19‐convalescent patients and healthy controls ( p &lt; .0001). Comparable results were obtained with M‐ or S‐peptides, the latter almost comparably recalled IL‐2, IFN‐γ, and IL‐13 responses in WB of vaccinees. Analysis 10 months as opposed to 10 weeks after COVID‐19, but not allergic disease status, positively correlated with IL‐13 recall responses. WB cytokine responses correlated with cytokine and proliferation responses of PBMC. Antigen‐induced neo‐expression of the C‐type lectin CD69 on CD4 + ( p &lt; .0001) and CD8 + ( p = .0002) T cells informed best about the SARS‐CoV‐2 exposure status with additional benefit coming from CD25 upregulation. Conclusion Along with N‐ and S‐peptide‐induced IL‐2 and CD69 neo‐expression, we suggest to include the type 2 cytokine IL‐13 as T‐cellular recall marker for SARS‐CoV‐2 specific T‐cellular immune responses after infection and vaccination.
Childcare and Employment Disruptions in 2020 Among Caregivers of Children With and Without Special Health Care Needs
Authors: Caleb Easterly, Doyoung Kim, Michael J. Steiner, Neal A. deJong
Journal: JAMA Pediatrics (2022)

Results | The 2 NDDs that had the largest association with bullying exposure were ASD and ADHD (Figure 1).Special health care needs (SHCN) (OR, 1.9; 95% CI, 1.6-2.2),adverse childhood experience (OR, 1.6; 95% CI, 1.4-1.9),and disadvantaged neighborhoods (OR, 1.3; 95% CI, 1.1-1.5)were associated with a higher risk of being bullied, while older age was associated with a lower risk for only some children (OR, 0.8; 95% CI, 0.7-0.9).Notably, the interaction analyses showed that older children with ASD (age 12-17 years) were more likely to be bullied than younger children with ASD (6-11 years).In addition, disadvantaged neighborhoods and lack of SHCN further increased the association of ASD with the risk of bullying exposure.Figure 2 illustrates how age or SHCN interacted with the association between risk of being bullied and ASD.The association between bullying exposure and ADHD was not modified by any sociodemographic factors, neighborhood-related features, or SHCN.Discussion | Some individual attributes, such as age or SHCN, could exert different effects between children with ASD and their non-ASD peers.Individuals with ASD who do not have SHCN may be those with less severe symptoms.Compared with children with low-functioning ASD, they may be more likely to attend public schools, where bullying is more prevalent, especially in areas with low socioeconomic status. 5 Note that the causal relationship between SHCN and bullying exposure cannot be clarified in our cross-sectional study.However, these findings are consistent with previous findings that children with high-functioning ASD who attended public schools are more likely to be bullied than other children with ASD. 6 Older age could be a protective factor for children who do not have ASD, but it could be a risk factor for children with ASD.Additional research is indicated about bullying prevention programs targeting identified risk factors for children with ASD.
What tests should be used to assess functional performance in youth and young adults following anterior cruciate ligament or meniscal injury? A systematic review of measurement properties for the OPTIKNEE consensus
Authors: Bjørnar Berg, Anouk P Urhausen, Britt Elin Øiestad, Jackie L Whittaker, Adam G Culvenor, Ewa M Roos, Kay M Crossley, Carsten B Juhl, May Arna Risberg
Journal: British Journal of Sports Medicine (2022)

To critically appraise and summarise measurement properties of functional performance tests in individuals following anterior cruciate ligament (ACL) or meniscal injury.Systematic review.Systematic searches were performed in Medline (Ovid), Embase (Ovid), CINAHL (EBSCO) and SPORTSDiscus (EBSCO) on 7 July 2021.Studies evaluating at least one measurement property of a functional performance test including individuals following an ACL tear or meniscal injury with a mean injury age of ≤30 years. The COnsensus-based Standards for the selection of health Measurement INstruments Risk of Bias checklist was used to assess methodological quality. A modified Grading of Recommendations Assessment, Development and Evaluation assessed evidence quality.Thirty studies evaluating 26 functional performance tests following ACL injury were included. No studies were found in individuals with an isolated meniscal injury. Included studies evaluated reliability (n=5), measurement error (n=3), construct validity (n=26), structural validity (n=1) and responsiveness (n=1). The Single Leg Hop and Crossover Hop tests showed sufficient intrarater reliability (high and moderate quality evidence, respectively), construct validity (low-quality and moderate-quality evidence, respectively) and responsiveness (low-quality evidence).Frequently used functional performance tests for individuals with ACL or meniscal injury lack evidence supporting their measurement properties. The Single Leg Hop and Crossover Hop are currently the most promising tests following ACL injury. High-quality studies are required to facilitate stronger recommendations of performance-based outcomes following ACL or meniscal injury.
Bacterial Darth Vader: May the force be with you
Authors: Kornelia Polyak
Journal: Cancer Cell (2022)

The microbiome has a major impact on tumor progression, yet the mechanisms are poorly defined. Fu et al. report in Cell that intracellular bacteria in a breast cancer model promote metastasis via reorganizing the cytoskeleton to enhance resistance to mechanical stress, thereby facilitating survival in the circulation during dissemination. The microbiome has a major impact on tumor progression, yet the mechanisms are poorly defined. Fu et al. report in Cell that intracellular bacteria in a breast cancer model promote metastasis via reorganizing the cytoskeleton to enhance resistance to mechanical stress, thereby facilitating survival in the circulation during dissemination. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancerFu et al.CellApril 7, 2022In BriefTumor-resident intracellular bacteria enhance survival of circulating tumor cells by cytoskeleton reorganization. They promote metastasis but are not required for primary tumor growth in a murine breast cancer model. Full-Text PDF Open Archive
The effect of achieving serological remission on subsequent risk of relapse, end-stage renal disease and mortality in ANCA-associated vasculitis: a target trial emulation study
Authors: Gregory McDermott, Xiaoqing Fu, Claire Cook, Catherine Ahola, Brett Doliner, Jennifer Hanberg, John H Stone, Hyon K Choi, Yuqing Zhang, Zachary S Wallace
Journal: Annals of the Rheumatic Diseases (2022)

To evaluate the effect of achieving a negative postinduction antineutrophil cytoplasmic antibody ANCA) assay on the risk of relapse, end-stage renal disease (ESRD) and death in ANCA-associated vasculitis (AAV).We emulated a target trial using observational data from the Mass General Brigham AAV cohort comparing patients who achieved versus did not achieve serological remission (negative ANCA assay) within 180 days of induction. Outcomes were relapse, ESRD or death within 5 years, obtained from medical records, the US Renal Data System and the National Death Index. We placed a 'clone' of each patient in both trial arms, censored those deviating from their assigned protocol and weighted each by the inverse probability of censoring. Outcomes were assessed by pooled logistic regression.The study included 506 patients with AAV. The mean age was 61 years (SD 18) and the majority were women (58%), white (87%), myeloperoxidase-ANCA+ (72%) and had renal involvement (68%). Rituximab (59%) or cyclophosphamide (33%) was most often used for induction treatment. Within 5 years, 81 (16%) died, 51 (10%) had ESRD and 64 (13%) had relapse. Patients treated to a negative ANCA assay within 180 days had HR 0.55 (95% CI 0.38 to 0.81) for relapse and HR 0.87 (95% CI 0.61 to 1.25) for the composite of ESRD or death within 5 years.In this emulated target trial from a large AAV cohort, achieving serological remission within 180 days of induction was associated with lower risk of relapse, but no statistically significant difference in ESRD or mortality outcomes.
Continuous Glucose Monitoring Metrics and Birth Weight: Informing Management of Type 1 Diabetes Throughout Pregnancy
Authors: Eleanor M. Scott, Helen R. Murphy, Karl H. Kristensen, Denice S. Feig, Karin Kjölhede, Linda Englund-Ögge, Kerstin E. Berntorp, Graham R. Law
Journal: Diabetes Care (2022)

To determine gestational weekly changes in continuous glucose monitoring (CGM) metrics and 24-h glucose profiles and their relationship to infant birth weight in pregnant women with type 1 diabetes.An analysis of >10.5 million CGM glucose measures from 386 pregnant women with type 1 diabetes from two international multicenter studies was performed. CGM glucose metrics and 24-h glucose profiles were calculated for each gestational week, and the relationship to normal (10-90th percentile) and large (>90th percentile) for gestational age (LGA) birth weight infants was determined.Mean CGM glucose concentration fell and percentage of time spent in the pregnancy target range of 3.5-7.8 mmol/L (63-140 mg/dL) increased in the first 10 weeks of pregnancy and plateaued until 28 weeks of gestation, before further improvement in mean glucose and percentage of time in range until delivery. Maternal CGM glucose metrics diverged at 10 weeks of gestation, with significantly lower mean CGM glucose concentration (7.1 mmol/L; 95% CI 7.05-7.15 [127.8 mg/dL; 95% CI 126.9-128.7] vs. 7.5 mmol/L; 95% CI 7.45-7.55 [135 mg/dL; 95% CI 134.1-135.9]) and higher percentage of time in range (55%; 95% CI 54-56 vs. 50%; 95% CI 49-51) in women who had normal versus LGA. The 24-h glucose profiles were significantly higher across the day from 10 weeks of gestation in LGA.Normal birth weight is associated with achieving significantly lower mean CGM glucose concentration across the 24-h day and higher CGM time in range from before the end of the first trimester, emphasizing the need for a shift in clinical management, with increased focus on using weekly CGM glucose targets for optimizing maternal glycemia from early pregnancy.
Genetic tracing reveals transcription factor Foxp3-dependent and Foxp3-independent functionality of peripherally induced Treg cells
Authors: Joris van der Veeken, Clarissa Campbell, Yuri Pritykin, Michail Schizas, Jacob Verter, Wei Hu, Zhong-Min Wang, Fanny Matheis, Daniel Mucida, Louis-Marie Charbonnier, Talal A. Chatila, Alexander Y. Rudensky
Journal: Immunity (2022)
Fully Automated 3D Segmentation and Diffeomorphic Medial Modeling of the Left Ventricle Mitral Valve Complex in Ischemic Mitral Regurgitation
Authors: Ahmed H. Aly, Pulkit Khandelwal, Abdullah H. Aly, Takayuki Kawashima, Kazuki Mori, Yoshiaki Saito, Judy Hung, Joseph H. Gorman, Alison M. Pouch, Robert C. Gorman, Paul A. Yushkevich
Journal: Medical Image Analysis (2022)
An injectable conductive hydrogel restores electrical transmission at myocardial infarct site to preserve cardiac function and enhance repair
Authors: Linghong Zhang, Tao Li, Yan Yu, Kun Shi, Zhongwu Bei, Yongjun Qian, Zhiyong Qian
Journal: Bioactive Materials (2022)

Myocardial infarction (MI) leads to massive cardiomyocyte death and deposition of collagen fibers. This fibrous tissue disrupts electrical signaling in the myocardium, leading to cardiac systolic and diastolic dysfunction, as well as arrhythmias. Conductive hydrogels are a promising therapeutic strategy for MI. Here, we prepared a highly water-soluble conductive material (GP) by grafting polypyrrole (PPy) onto non-conductive gelatin. This component was added to the gel system formed by the Schiff base reaction between oxidized xanthan gum (OXG) and gelatin to construct an injectable conductive hydrogel. The prepared self-healing OGGP3 (3 wt% GP) hydrogel had good biocompatibility, elastic modulus, and electrical conductivity that matched the natural heart. The prepared biomaterials were injected into the rat myocardial scar tissue 2 days after MI. We found that the cardiac function of the rats treated with OGGP3 was improved, making it more difficult to induce arrhythmias. The electrical resistivity of myocardial fibrous tissue was reduced, and the conduction velocity of myocardial tissue was increased. Histological analysis showed reduced infarct size, increased left ventricular wall thickness, increased vessel density, and decreased inflammatory response in the infarcted area. Our findings clearly demonstrate that the OGGP3 hydrogel attenuates ventricular remodeling and inhibits infarct dilation, thus showing its potential for the treatment of MI.
Brain lesions disrupting addiction map to a common human brain circuit
Authors: Juho Joutsa, Khaled Moussawi, Shan H. Siddiqi, Amir Abdolahi, William Drew, Alexander L. Cohen, Thomas J. Ross, Harshawardhan U. Deshpande, Henry Z. Wang, Joel Bruss, Elliot A. Stein, Nora D. Volkow, Jordan H. Grafman, Edwin van Wijngaarden, Aaron D. Boes, Michael D. Fox
Journal: Nature Medicine (2022)

Abstract Drug addiction is a public health crisis for which new treatments are urgently needed. In rare cases, regional brain damage can lead to addiction remission. These cases may be used to identify therapeutic targets for neuromodulation. We analyzed two cohorts of patients addicted to smoking at the time of focal brain damage (cohort 1 n = 67; cohort 2 n = 62). Lesion locations were mapped to a brain atlas and the brain network functionally connected to each lesion location was computed using human connectome data ( n = 1,000). Associations with addiction remission were identified. Generalizability was assessed using an independent cohort of patients with focal brain damage and alcohol addiction risk scores ( n = 186). Specificity was assessed through comparison to 37 other neuropsychological variables. Lesions disrupting smoking addiction occurred in many different brain locations but were characterized by a specific pattern of brain connectivity. This pattern involved positive connectivity to the dorsal cingulate, lateral prefrontal cortex, and insula and negative connectivity to the medial prefrontal and temporal cortex. This circuit was reproducible across independent lesion cohorts, associated with reduced alcohol addiction risk, and specific to addiction metrics. Hubs that best matched the connectivity profile for addiction remission were the paracingulate gyrus, left frontal operculum, and medial fronto-polar cortex. We conclude that brain lesions disrupting addiction map to a specific human brain circuit and that hubs in this circuit provide testable targets for therapeutic neuromodulation.
Errors in the Text and Key Points
Authors: Fabrizio Piazza, Jacob Hall, Sharon Sha
Journal: JAMA Neurology (2022)

Joshua R. Ehrlich, MD, MPH; Jenna Goldstein, BA; Bonnie K. Swenor, PhD, MPH; Heather Whitson, MD, MHS; Kenneth M. Langa, MD, PhD; Phillip Veliz, PhD
Standardisation of ACPA tests: evaluation of a new candidate reference preparation
Authors: Lieve Van Hoovels, Lucy Studholme, Bert Vander Cruyssen, Daniela Sieghart, Carolien Bonroy, Eszter Nagy, Rille Pullerits, Sasa Čučnik, Charlotte Dahle, Ingmar Heijnen, Luca Bernasconi, Farid Benkhadra, Laura Bogaert, Stefanie Van Den Bremt, Ann Van Liedekerke, Geert Vanheule, Johan Robbrecht, Claudine Wirth, Rüdiger Müller, Diego Kyburz, Christopher Sjöwall, Alf Kastbom, Rok Ješe, Boja Jovancevic, Emese Kiss, Peggy Jacques, Daniel Aletaha, Günter Steiner, Patrick Verschueren, Xavier Bossuyt
Journal: Annals of the Rheumatic Diseases (2022)

Commercial assays measuring antibodies to citrullinated protein/peptide (ACPA) show poor quantitative agreement. The diagnostic industry has never adopted the International Union of Immunological Societies-Centers for Disease Control and Prevention (IUIS-CDC) ACPA reference standard. Recently, the National Institute for Biological Standards and Control (NIBSC) prepared a new candidate ACPA standard (18/204). We evaluated both reference materials using different commercially available ACPA assays.